HIV and malaria are two of the most important infectious diseases worldwide, and are synergistic in sub- Saharan Africa. The overarching goal of this program project (P01) is to evaluate novel and strategic interventions to reduce the burden of malaria and improve HIV outcomes among children and pregnant women, the populations most affected by the overlap of these diseases. We hypothesize that treatment with HIV protease inhibitors (Pis) will lower the incidence of malaria and consequent morbidity in HIV-infected children and pregnant women compared to those treated with standard antiretroviral treatment. This hypothesis is based on the appreciation that malaria parasites and HIV express biochemically similar proteases and the observation that HIV Pis exert potent in vitro antimalarial activity. Second, we hypothesize that in HIV-uninfected children, chemopreventive therapy will offer strong protection against malaria without increased malarial morbidity after discontinuation of the intervention. Third, we hypothesize that intermittent or chronic antimalarial and Pi-based antiretroviral therapy will select for drug resistant parasites, and that different drugs will offer different selective pressures. Four interlinked studies to test these three hypotheses comprise our P01 projects: 1: Protease inhibitors for the prevention of malaria in HIV-infected children 2: Protease inhibitors to reduce malaria morbidity in HIV-infected pregnant women 3: Chemopreventive therapy for malaria in HIV-uninfected infants and children 4: Selection of drug resistant malaria parasites by antimalarial and HIV therapies The projects will enroll a total of 1600 participants and be implemented by a multidisciplinary, multinational team in Tororo, Uganda, a site of high malaria transmission. Administrative and data/statistics cores will support the 4 projects. The projects will be conducted in the context of proven malaria preventive strategies that are currently the standard of care for most of sub-Saharan Africa: 1) the use of chemoprophylaxis with trimethoprim-sulfamethoxazole in HIV-infected children and pregnant women, and 2) the use of insecticide treated nets. Our primary goal will be to build on current knowledge to establish new approaches to reduce HIV and malaria burden in sub-Saharan Africa, and to advance the public health approach to both diseases.